Stress contributes to myriad psychopathologies, including anxiety, depression, schizophrenia, and drug use relapse. A common thread binding these disorders appears to be the stress-associated alteration in cognitive processes, namely learning and memory. Considerable human and animal research has shown that the hippocampus, a brain structure necessary for the formation of stable declarative (or explicit) memory, is highly susceptible to stress. Rodent studies further indicate that stress impairs long-term potentiation (LTP), a leading candidate cellular mechanism of information storage, in the hippocampus. We have recently discovered that the amygdala plays a necessary, time-dependent role in the emergence of stress effects on hippocampal LTP and memory. Accordingly, we hypothesize that the amygdala is an important component of the central stress mechanism that regulates neurocognitive functioning. The long-term goal of this research is to construct a general experimental and theoretical basis for understanding how stress influences the hippocampusfrom synaptic plasticity to neural activity to behaviorand incorporate this in a systems-level model that can organize existing data, predict new results, and generalize to other cognitive processes impacted by stress. There are four specific aims of the project: (1) an IN VITRO ANALYSIS will investigate the central stress mechanism altering hippocampal LTP; (2) a BEHAVIORAL ANALYSIS will determine the nature of central stress mechanism influencing hippocampal memory; (3) a SINGLE UNIT ANALYSIS will relate stress effects on specific behaviors with the activity of hippocampal neurons; and (4) GENERALIZATION OF THE MODEL will test whether the central stress mechanism identified in the first three aims is applicable to other types of learning and memory. Information generated from this project would be of significance (1) from a basic scientific perspective, providing valuable insights into the neuronal substrates underlying stress effects on neurocognition; and (2) from an applied perspective, providing testable hypotheses for explaining neurobiological changes that occur during stressful situations, thereby allowing insights into and treatment of various stress-related disorders that severely limit the quality of human life in todays increasingly hectic and long-living society.